Combining terpenes and cannabinoids can give different effects than taking each individually. Here are 3 different ways that this can happen.

Last week I gave an introduction to the entourage effect. This effect describes how different molecules in cannabis interact with each other to give an effect that is “greater than the sum of its parts”. With a lot of misinformation on this topic, I promised to give more details on which aspects of it have actual scientific backing.

Although I will soon be going into specific examples of the entourage effect, I want to start by educating you on the mechanisms of how the entourage effect can actually work. Because the entourage effect actually describes a plethora of different observations, there are multiple mechanisms to take into consideration.

Every mechanism falls into one of three possible groups, described below. Note that I use THC as an example to explain the mechanisms, but not every example of the entourage effect necessarily has to involve THC.

  • Pharmacokinetic interactions: When another molecule in cannabis impacts the levels of THC (either in the blood or in the brain)
  • Direct pharmacodynamic interactions: When another molecule in cannabis modulates the effects of THC by binding to the same receptor.
  • Indirect pharmacodynamic interactions: When another molecule in cannabis modulates the effects of THC by binding to a different receptor.

Below, you can read about each mechanism in more detail.

Infographic: 3 mechanisms of the cannabis entourage effect - pharmacokinetic, direct pharmacodynamic and indirect pharmacodynamic.

1. Pharmacokinetic Mechanisms of the Entourage Effect

Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of a drug within the body. There are many examples where a drug can interfere with one of these processes for another drug. This is the most common type of drug-drug interaction.

The interaction between CBD and THC is one example of the pharmacokinetic mechanism. In vitro, CBD can inhibit the human CYP2C9 enzyme, which is one of the primary enzymes to metabolize THC. CBD pretreatment boosted blood and brain levels of THC in rats and mice. Interestingly, the increase in brain THC levels seemed to partially depend on giving CBD before THC, and not at the same time.

Does CBD actually change the pharmacokinetics of THC in humans? This is less clear. Several human studies showed no change in THC blood pharmacokinetics with CBD. However, we know from the animal studies that seeing an effect depends on the CBD dose, the cannabinoid ratio, and the timing that each is taken.

There are also rumors that terpenes such as myrcene can increase brain levels of THC. Despite my best efforts, I could find no data to back up this claim.

Although it is good to know that this mechanism exists, it is probably the least important of the three entourage effect mechanisms. It can only explain a small number of observations related to the entourage effect. I believe that the next two mechanisms have a much greater significance.

2. Direct Pharmacodynamic Mechanisms of the Entourage Effect

Phytocannabinoid cell targets - CBD & THC receptorsHere I am defining a direct pharmacodynamic mechanism as two molecules from cannabis interacting simultaneously at the same receptor. The CB1 receptor is the most well studied, but there may be direct pharmacodynamic effects at multiple receptors (the cheat of cannabinoid targets is attached here). Depending on the type of ligand the cannabinoid or terpene acts as, we may see different effects. We can classify these effects as antagonistic, additive, or synergistic.

  • Antagonistic Interaction

An antagonistic interaction is when one molecule in cannabis inhibits the effects of another molecule. This may happen when one molecule is an agonist, but the other is an antagonist or negative allosteric modulator.

For example, CBD can act in vitro as an antagonist and negative allosteric modulator to turn down CB1 receptor activation by THC.  Besides the CB1 receptor, there are several receptors where THC activation can be reduced by CBD: the CB2 receptor, GPR18  receptor, and GPR55 receptor. I will be exploring the consequences of this in a future article.

  • Additive Interaction

You can see several examples where THC and CBD do the same thing at a target (both agonists, both antagonists, etc.). For the most part, the potency of THC and CBD are similar at these targets. This means that 10 mg THC would have the same effect as 5 mg THC + 5 mg CBD, which would have the same effect as 10 mg CBD.

Although it is good to understand this concept (and I am including it for completeness sake), it is a poor example of the entourage effect. This is because the THC/CBD combination will not do anything that either molecule cannot do on its own.

  • Synergistic Interaction

Synergism is when a combination of molecules has a greater than additive effect. There are surprisingly little published data about synergistic interactions at the CB1 receptor. However, this has recently been explored by a cannabis company called ebbu.

In a 2016 press release, ebbu reported that they found 8 different terpenes that increase the potency of THC at CB1 and 3 other cannabinoids that increase the effect of THC at CB1. Presumably, these molecules are acting as positive allosteric modulators of THC. If so, it is possible that combining a low dose of THC with enough of the terpene could have the same effect as a high dose of THC. We will have to wait and see whether ebbu releases any more details on this.

There are even less data on whether terpenes and cannabinoids can have synergistic actions at other targets besides CB1. The same ebbu press release from above indicated that one terpene synergizes with THC at TRPV1, which is a receptor important for pain and epilepsy.

3. Indirect Pharmacodynamic Mechanisms of the Entourage Effect

By an indirect mechanism, I mean that two cannabis molecules are interacting through two different receptors. To me, this is where the most exciting examples of the entourage effect lie. It is not just about turning up or down activation of the CB1 receptor, but tweaking the downstream effects of its activation.

CB1 receptor activation can impact just about every other neurotransmitter system. The approach ebbu takes to look only at how terpenes/other cannabinoids can increase CB1 receptor activation has a huge limitation. If you increase CB1 receptor activation, you are increasing all of the effects, good and bad.

[Side note: I am assuming that they have not discovered examples of allosteric bias – where the allosteric modulator actually changes the signaling pathway activated by the CB1 receptor]

On the other hand, an indirect pharmacodynamic mechanism allows modulation of specific effects of THC in a specific neurotransmitter system. Several of these mechanisms have already been proposed:

  • CBD & CBD-A reduce anxiety produced by THC through the serotonin system
  • CBD reduces psychosis-like effects of THC through the dopamine system
  • Myrcene amplifies sedative effects of THC through the GABA system
  • Pinene improves THC-induced memory deficits through the acetylcholine system

I’m not going into detail on these now, because each one (and others) will have their own article exploring the scientific evidence. I hope you join me as I continue this series of articles on the cannabis entourage effect…join the mailing list or follow me on Facebook to stay updated!

[Featured image credit: Max Pixel]

Last modified: July 30, 2017

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